Ly Annie, Hotchkiss Hayden, Prévost Emily D, Pelletier Julianne, Deming Melissa, Murib Luma, Root David H
Department of Psychology and Neuroscience, University of Colorado Boulder, 2860 Wilderness Pl, Boulder, CO 80301.
bioRxiv. 2025 Jan 2:2025.01.01.631006. doi: 10.1101/2025.01.01.631006.
Conditioned suppression is a useful paradigm for measuring learned avoidance. In most conditioned suppression studies, forward conditioning is used where a cue predicts an aversive stimulus. However, backward conditioning, in which an aversive stimulus predicts a cue, provides unique insights into learned avoidance due to its influence on both conditioned excitation and inhibition. We trained mice to consume sucrose in context A, associated an aversive stimulus in context B to few or many forward or backwards paired cues (CS+), and then tested for conditioned suppression in context A in response to the CS+. We found that few or many forward CS+ and few backward CS+ produced conditioned suppression, but many backwards cues did not. Administration of diazepam, a positive allosteric modulator of the GABA-A receptor, prevented conditioned suppression to the backward CS+ but not to the forward CS+. Furthermore, freezing behavior was observed in response to the forward CS+ but not the backward CS+, and diazepam had no effect on freezing or locomotion. We next examined BNST GABA neurons for potential sensitivity to backwards cues and conditioned suppression. VGaT BNST signaling increased in response to sucrose licks during the backward CS+ but not to licks outside the CS+ and not to the backward CS+ onset or offset. Using designer receptors, we found that BNST VGaT neuron activation, but not its inhibition, prevented backward conditioned suppression expression. We conclude that backward conditioned suppression is dependent on both positive allosteric modulation of GABA on GABA-A receptors by diazepam and BNST GABA neurons.
条件性抑制是一种用于测量习得性回避的有用范式。在大多数条件性抑制研究中，采用正向条件作用，即一个线索预示着厌恶刺激。然而，反向条件作用（其中厌恶刺激预示着一个线索）由于其对条件性兴奋和抑制的影响，为习得性回避提供了独特的见解。我们训练小鼠在情境A中消耗蔗糖，将情境B中的厌恶刺激与少量或大量正向或反向配对线索（CS+）相关联，然后在情境A中测试对CS+的条件性抑制。我们发现少量或大量正向CS+以及少量反向CS+会产生条件性抑制，但大量反向线索则不会。给予地西泮（一种GABA-A受体的正向变构调节剂）可阻止对反向CS+的条件性抑制，但对正向CS+无效。此外，观察到对正向CS+有僵住行为，但对反向CS+没有，并且地西泮对僵住或运动没有影响。接下来，我们检查了终纹床核GABA能神经元对反向线索和条件性抑制的潜在敏感性。在反向CS+期间，VGaT终纹床核信号响应蔗糖舔舐而增加，但对CS+之外的舔舐、反向CS+的开始或结束均无反应。使用设计受体，我们发现终纹床核VGaT神经元的激活而非抑制可阻止反向条件性抑制的表达。我们得出结论，反向条件性抑制既依赖于地西泮对GABA-A受体上GABA的正向变构调节，也依赖于终纹床核GABA能神经元。
